Abstract
We examined the genotype-phenotype interactions of Cyp51+/− mice carrying one functional allele of lanosterol 14α-demethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/− and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/− mice and controls fed for 16 weeks with three diets and applied linear regression modeling. We used 3 predictor variables (genotype, sex, diet), and 39 response variables corresponding to the organ characteristics (7), plasma parameters (7), and hepatic gene expression (25). We observed significant differences between Cyp51+/− and wild-type mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/− males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/− females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls. We observed elevated hepatocyte apoptosis, mitosis and lipid infiltration in heterozygous knockouts of both sexes. The Cyp51+/− females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet. Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.
Highlights
Cholesterol, an essential compound of cell membranes, regulates permeability, fluidity, and membrane signaling capacity [1], is a precursor of steroid hormones and bile acids, and plays an important role in cell proliferation [2,3]
The Cyp51+/2 heterozygotes show a decreased expression of Cyp51 mRNA and protein compared to the Cyp51+/+ controls on each diet (Figure 2), indicating that Cyp51 is transcribed from both alleles with no compensatory mechanisms in Cyp51+/2 mice
Cyp51+/2 females remained leaner than wild-type controls, with the plasma lipid profile similar to that of controls
Summary
Cholesterol, an essential compound of cell membranes, regulates permeability, fluidity, and membrane signaling capacity [1], is a precursor of steroid hormones and bile acids, and plays an important role in cell proliferation [2,3]. The lipid homeostasis is performed mainly by the liver, the major organ of lipid clearance [6] and synthesis. Almost 40% of the cholesterol is synthesized in the murine liver [7], and the pathway is well conserved in mammals. Most murine studies focus on the complete knockout models that are unlikely to be found in humans, due to the lethal developmental phenotype, while mice heterozygous for the cholesterol-linked genes seldom present a distinct phenotype (Figure 1). The cholesterol homeostasis in humans exhibits examples where abnormalities manifest with the heterozygous variants, such as in the genes of cholesterol synthesis (HMGCR, DHCR7, DHCR24 and CYP51A1), where polymorphisms associate with preterm delivery or low birth weight [12,13,14]
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